Embolic compositions with non-cyanoacrylate rheology modifying agents

ABSTRACT

Compositions for embolization are disclosed herein. The compositions disclosed can have a matrix-forming component, a solid-aggregate material, and a rheology modifying agent, wherein the matrix-forming component includes at least alkyl cyanoacrylate monomers, a stabilizer, and a plasticizer, and the solid-aggregate material includes at least a radiopacifier. The composition and a method of administering the composition are useful for treating vasculature abnormalities, particularly when the composition solidifies upon contact with an ionic environment, such as blood.

FIELD OF THE INVENTION

The present invention relates generally to polymer compositions, andmore particularly, liquid polymer compositions capable of forming asolid embolic block upon administration in an ionic environment, such asblood. The composition can be used for treating vascular abnormalities,including brain aneurysms. In particular, the compositions of thepresent invention comprise a matrix-forming component and asolid-aggregate material, which can combine to form an emboliccomposition upon administration.

BACKGROUND OF THE INVENTION

Vascular embolization often is the chosen method for controllingbleeding in the blood vessels or occluding blood supply to solid masstumors or vascular aneurysms. Currently available therapeutic regimensfor treating solid mass tumors can be difficult to administer,particularly depending on the properties of the embolic, or bulking,composition used. Aneurysms, arteriovenous malformations (“AVMs”) andother vascular abnormalities, for example, vascular tumors, can bedifficult to treat. Treatment of lesions and growths that occur in thebrain or brain stem is especially complicated due to the particularlysensitive nature of the surrounding tissue.

Cyanoacrylate adhesives have been used for treatment of AVMs and othervascular abnormalities for almost thirty years. The usefulness of thesecompositions has been limited by cytotoxicity and the amount of heatgenerated by polymerization. Recent developments in the formulation ofcyanoacrylate compositions have improved the usefulness of suchcompositions in treating vascular disease. For example, U.S. Pat. No.6,015,541, issued Jan. 18, 2000, describes a radioactive composition fortreating solid mass tumors comprising a biocompatible free polymer, abiocompatible solvent, and about 0.1 to about 25 weight percent of awater in soluble radioisotope. The biocompatible polymer can be acyanoacrylate free polymer variant and the composition containsn-butyl-2-cyanoacrylate (NBCA) in combination with an iridium isotope.Although such a composition was demonstrated to have effect on a solidmass tumor in a rabbit, the viscosity and suspension properties of thecomposition were less than desirable. Another disadvantage is that theiridium isotope settled within several seconds after mixing, requiringconstant, gentle agitation to prepare a prolonged suspension.

A composition including 2-hexyl cyanoacrylate and gold was described inU.S. Pat. No. 6,037,366, issued Mar. 14, 2000. The cyanoacrylatecomposition demonstrated improved cohesion properties compared toprevious compositions. Administration of such compositions involvedmixing two separate components of material immediately prior toadministration into the AVM. One component contained cyanoacrylateliquid monomer containing pure phosphoric acid hydroquinone andp-methoxyphenol. The second component contained pure powdered gold, asmall amount of pre-polymerized cyanoacrylate polymer and a fatty acid,ethyl myristate. The improved cohesion properties kept the materialstogether during the time required for polymerization. Althoughincorporation of a small amount of pre-polymerized cyanoacrylate monomeris mentioned in the composition, there is no mention of anynon-cyanoacrylate rheology or viscosity modifying agent.

Alkyl cyanoacrylate compositions in general were described inInternational PCT publication WO 00/44287, published on Aug. 3, 2000.The compositions contained the alkyl cyanoacrylate and at least oneinhibitor, and a second component comprised of a resultant aggregatestructure formed from an alkyl cyanoacrylate monomer, an alkylesterified fatty acid and an opacificant agent. The composition formedthe resultant aggregate structure upon contact with blood. Althoughthese compositions demonstrate improved properties over priorcompositions, inadvertent tissue adhesion to microcatheter deliverydevices used to administer such compositions remains a problem. There isno suggestion or recognition that such properties can be improved by anon-cyanoacrylate rheology modifying agent.

Accordingly, there remains a need for an improved composition fortreating vascular abnormalities, such as AVMs or brain aneurysms. Theimproved composition would have properties of apparent viscosity between25 cP and 2000 cP, improved cohesiveness, improved suspension of denseradiopacifier powders, and radiopacity. In addition, the compositionwould form a solid composition possessing improved hydrolytic stabilityupon contact with an aqueous environment, for example, blood.

SUMMARY OF THE INVENTION

The invention relates to a composition comprising a matrix-formingcomponent and optionally a solid-aggregate material. The matrix-formingcomponent can comprise liquid alkyl cyanoacrylate monomers and at leasta stabilizer and a plasticizer. The composition can incorporate asolid-aggregate material with the matrix-forming component, whichtypically consists of at least a radiopaque powder, i.e. aradiopacifier. A rheology modifying agent also can be incorporated intothe composition, either in combination with the matrix-forming componentor with the solid-aggregate material. The rheology modifying agent canbe a non-cyanoacrylate polymer or a fine inorganic particulate compound,other than the radiopacifier.

The composition is useful in a therapeutic regimen for treating vascularabnormalities. Vascular abnormalities that can be treated byadministration of the composition include, for example, AVMs, aneurysms,fistulas, and tumors. Upon contact with an ionic environment, the liquidcomposition rapidly increases in viscosity, forming a solidifiedcomposition having the consistency of a rubbery polymeric matrix.

The method of the invention includes administering the composition fortissue bulking, filling, or occluding, either partially or entirely, avolume or cavity in a mass. Typically, the volume or cavity filled bythe method of the present invention is a lumen or passageway in thebody, for example, a blood vessel, a duct, an aneurysm, or a fistula.The solid composition formed in the method of the invention is usefulfor abating disease of the vascular tissues or by cutting off the bloodsupply to undesired tissue. A tumor or abnormality is occluded bycutting off the blood supply to the diseased area, resulting indiminished growth or death of the tumor or abnormality.

The method of the invention also includes administering the compositionto embolize a vascular space. The composition is administered to apatient, typically in need of treatment for vascular abnormalities, toform an embolic block at the site of diseased, damaged, or otherwisecompromised vasculature.

The above and other aspects, advantages, and novel features of theinvention will become apparent from the following detailed descriptionof the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Therefore, in one aspect, the invention relates to matrix-formingcomponents comprising an alkyl cyanoacrylate monomer in combination withat least a stabilizer and a plasticizer. The matrix-forming componentsalso can include a polymeric rheology modifying agent. Thematrix-forming components can be used with one or more solid-aggregatematerials. All the materials used are either incorporated into a singleinjectable embolic composition along with the matrix-forming componentsor can be included in one of a number of separately packaged mixturesthat are combined prior to use to form the embolic composition. Thestabilizing component is comprised of an acidic stabilizer, a freeradical inhibitor, an antioxidant, or a mixture thereof. The plasticizercan be selected from a group of polymeric or non-polymeric compoundsthat impart flexibility, prevent brittleness, reduce adhesiveness tocatheter delivery devices, and are compatible with alkyl cyanoacrylatemonomers. The solid-aggregate material comprises a radiopacifier, andalso can include a rheology modifying agent.

The rheology modifying agent is a non-cyanoacrylate polymer or finesolid particulate compound that is not radiopaque. The rheologymodifying agent is capable of increasing the Newtonian viscosity of thecomposition and/or capable of imparting non-Newtonian behavior upon theliquid composition, such that it demonstrates thixotropic,pseudo-plastic, or plastic fluid behavior. Fluids that exhibit suchbehaviors generally can be classified as “shear thinning.”

The rheology modifying agent can impart properties on the liquidinjectable composition of an apparent viscosity of between 25 cP and2000 cP, and preferably between about 100 cP and about 300 cP, improvedcohesiveness over cyanoacrylate-polymerizing compositions, improvedsuspension and stability of dense radiopacifying powders, and additionalradiopacity. The rheology modifying agent may also impart an improvedsurface tension of the composition as it solidifies.

In this aspect of the invention, the rheology modifying agent isoptionally incorporated into the matrix-forming component or thesolid-aggregate material, provided that the composition contains atleast one rheology modifying agent. The composition is renderedradiopaque by including the radiopacifier, which typically comprises afine powder or sub-micron sized particles having a radiopaque nature.Typically, the radiopacifer component has high x-ray absorbance, eitheralone, or in combination, with iodinated oils.

The composition can also be useful for bulking muscular tissues. Tissuesthat can be treated include smooth muscle sphincters and other tissuesthat can benefit from volumetric augmentation. The composition isparticularly useful when a radiopacifier is incorporated in thecomposition for visualization of the administration of the composition.

In another aspect, the method of the invention relates to embolizing avascular space, or cavity, by administering the composition of theinvention. The method can be accomplished by combining thematrix-forming components of the invention with one or moresolid-aggregate materials. In particular, the matrix-forming components,including at least liquid cyanoacrylate monomers, a stabilizer, and aplasticizer, are exposed to a solid-aggregate material that comprises atleast a radiopacifier. The composition is typically a liquid injectablecomposition that solidifies upon contact with an ionic environment, forexample, blood. Either the matrix-forming component or thesolid-aggregate material contains a non-cyanoacrylate compound, whichimparts improved rheology, cohesiveness, suspension stability, andradiopacity properties of the liquid injectable composition. Inaddition, the inclusion of a non-cyanoacrylate polymer compound canimpart an improved hydrolytic stability on the solidified compositionrendered in the body.

In another aspect, the method of the invention is useful for stabilizingor mitigating rupture of an aneurysm. The composition of the inventioncan be used to occlude the interior space of an unruptured or previouslyruptured aneurysm. Methods of non-surgical treatment using non-alkylcyanoacrylate compositions are described in J. Vascular and InterventionRadiology, 10:891-894, July-August 1999.

The composition is delivered by any suitable device for administering aliquid composition. One example of a suitable device presently availableis a microcatheter, such as the EXCELSIOR™ microcatheter (TargetTherapeutics, Inc., Fremont, Calif., U.S.A.). The invention also canemploy any method using any number of commercially available devices,for example, catheters, catheter coils, catheter wires, stents, orcatheter balloons. An example of a commercially available devicesuitable for augmenting the delivery of the composition is the SENTRY™Occlusion Balloon System, available from Target Therapeutics, Inc.,Fremont, Calif., U.S.A. The method can be used in combination withaffixing therapeutics, chemotherapeutics, radiation delivery devices,and gene therapy compositions, which are delivered to the desiredlocation in proximity with the composition of the invention.

As used herein, the terms “adhesion” or “adhesive” mean thecharacteristic or tendency of a material to be attracted to the surfaceof a second material. Adhesion occurs as the result of interactionsbetween two materials. Depending on the characteristics of the secondmaterial relative to the first material, adhesion may or may not occur.For a single material, e.g. the composition of the present invention,the presence of adhesion is demonstrated by a material sticking to thewall of a lumen of a blood vessel, i.e. there is adhesion between thematerial and the lumen wall. Conversely, the absence of adhesion isdemonstrated for the same material where a microcatheter tip used todeposit the material can be removed from the material, i.e., there islittle adhesion between the material and microcatheter tip.

As used herein, the term “alkyl” refers to a carbon chain of one toeighteen atoms, where the carbon atoms can be linear or branched.

As used herein, the term “ionic environment” refers to an environmentthat contains ions. The term “nonionic” refers to an environment that isdevoid of charged ions, or where the charged ions are complexed withother molecules, which effectively neutralize their charge. For example,a solution of water and a sugar, such as dextrose, and blood is an ionicenvironment.

As used herein, the term “lower-alkyl” refers to a carbon chain of oneto eight carbon atoms where the carbon atoms can be linear or branched.Examples of lower-alkyl moieties include, but are not limited to,methyl, ethyl, n-butyl, isobutyl, pentyl, n-hexyl, 2-hexyl, n-heptyl,2-heptyl, n-octyl, and 2-octyl.

As used herein, the term “branched alkyl” refers to a carbon chain ofone to eighteen carbon atoms where the carbon chain contains at leastone secondary or tertiary substituted carbon atom, for example, 2-hexyl,isobutyl, 2-heptyl, 2-octyl, and the like.

As used herein, the term “cohesion” or “cohesive” means thecharacteristic or tendency of a material to stick together to itself.For example, this characteristic is demonstrated by a material orcomposition remaining intact as a single mass when introduced into astationary fluid, or a fluid stream in motion, such as blood. Lack ofcohesive integrity results in the composition breaking up into multiplesmaller subunits.

As used herein, the term “matrix-forming component” refers to theassemblage of one or more compounds, and preferably not more than 5 or 6compounds, incorporated into the continuous phase of a solidifiedembolic composition.

As used herein, the term “solid-aggregate material” refers to one ormore solid particulate compounds or matter, and preferably not more than1 or 2 compounds, that are separate from, but generally dispersedwithin, the matrix of a solidified embolic composition.

The term “bulking agent” as used herein refers to a non-naturallyoccurring composition introduced into muscular, connective, or fattytissues for the purpose of increasing the volume of such tissues.

As used herein, the term “embolic agent” refers to a non-naturallyoccurring composition introduced into a body cavity or the lumen of ablood vessel, duct, fistula, aneurysm, or other like body passagewaysfor the purpose of forming an embolic composition.

The term “embolic composition” as used herein refers to the assemblageof the matrix-forming components and the solid-aggregate materials.

As used herein, the term “embolic block” or “embolic blockage” orocclusion refers to the end result from the administration of acomposition useful as an embolic agent. The resulting embolic blockmechanically blocks, totally or partially, the lumen of a blood vessel,duct, fistula or other like body passageways or, in a like manner, formsan occlusion within a cavity, such as an aneurysm.

As used herein, the term “alkyl cyanoacrylate monomer” refers to thechemical entity of the general structure H₂C═C(CN)—C(O)O—R, where R isan alkyl moiety of one to eighteen carbon atoms, linear or branched,saturated or unsaturated, having the physical characteristic of beingable to form the corresponding alkyl cyanoacrylate polymer. As used inthe singular form, “alkyl cyanoacrylate monomer” also is intended torefer to more than one monomer, as would be understood by one with skillin the art.

As used herein, the term “alkyl cyanoacrylate polymer” means an oligomeror polymer resulting from the polymerization of an alkyl cyanoacrylatemonomer.

As used herein, the term “radiopacifer” is a compound or compositionthat selectively absorbs or deflects radiation making the materialvisible under x-ray, or any like imaging technique. Typically, suchagents include iodinated oils and brominated oils, and mixtures thereof,as well as commercially available compositions, such as PANTOPAQUE®,LIPIODOL® (Laboratories Guerbet, Aulnay-sous-Bois, France), andETHIODOL® (Savage Laboratories, Melville, Md., U.S.A.). Thesecommercially available materials render the composition radiopaque andalso can dilute the amount of a liquid monomer thereby slowing the rateof polymerization. In addition, certain metals such as gold, platinum,tantalum, titanium, tungsten, barium sulfate, and the like, and mixturesthereof, have properties enabling them to act as radiopacifiers.

As used herein, the term “polymerization” refers to the chemical processwhere identical monomer units react chemically to form larger moleculescomprised of said monomeric units as oligomers or polymers.

As used herein, the term “stabilizer” or “stabilizing component” means acompound or composition that can stop or slow down the rate ofpolymerization. Examples of such agents are phosphoric acid andhydroquinone.

As used herein, the term “vascular space” or “cavity” refers to anunfilled volume or hollow void in a mass. Examples of such cavitiesinclude, but are not limited by the following, as existing space withina mass, such as the lumen of a blood vessel, the sac of an aneurysm, aspace created by a transiently placed external device, such as acatheter, needle, canula, or like device, a space created by aprocedure, such as an excision or like procedure, a physical voidcreated by implantation of an object, such as a stent or like device, ora void created by the composition.

As used herein, the term “stability” refers to the ability of a monomercomponent to resist degradation or polymerization after preparation butprior to use.

The alkyl cyanoacrylate monomers of the present invention are alreadyknown. The monomers can be prepared by forming the desired precursorester, the corresponding alcohol and cyanoacetic acid. The reaction ofthe alkyl alcohol with the cyanoacetic acid forms an alkyl cyanoacetate,which can be converted into the desired alkyl cyanoacrylate compound.The preparation of the alkyl cyanoacrylate compounds has been describedin U.S. Pat. No. 6,015,541, issued Jan. 18, 2000, U.S. Pat. No.6,037,366, issued Mar. 14, 2000, and PCT International Publication WO00/44287, published Aug. 3, 2000. Starting materials for preparing thealkyl cyanoacrylate monomer are commercially available from, forexample, Aldrich Chemical Company, Sigma Chemical Company, or FlukaChemical Company, or can be prepared by the procedures known to thosewith skill in the art.

Briefly, an alkyl alcohol, containing from 1 to 18 carbons, is reactedwith cyanoacetic acid. The alcohol can contain from 1 to 18 carbons, forexample, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, deca, undeca, dodeca, trideca, tetradeca, pentadeca, hexadeca,and octadeca, and the like. Particularly advantageous alcohols aredescribed in U.S. Pat. No. 3,728,375 entitled “Cyanoacrylate AdhesiveCompositions”, which is herein incorporated by reference in itsentirety. Especially preferred alcohols are n-butyl, isobutyl, and2-hexyl alcohols. About one molar equivalent of the alkyl alcohol isreacted with one mole of cyanoacetic acid in an organic solvent. Acatalytic amount of p-tolulene sulfonic acid is added and the mixture isstirred and heated to reflux to afford the desired alkyl cyanoacetate.

The alkyl cyanoacetate undergoes Knoevenagel-type reaction to providethe alkyl cyanoacrylate. About one molar equivalent of the formaldehydeis dissolved in solvent, such as an organic alcohol, for example,methanol. The formaldehyde solution is reacted with about one molarequivalent of alkyl cyanoacetate in a dropwise manner, with stirring, toyield the desired alkyl cyanoacetate polymer. The reaction system istreated with trace amounts of the sulfur dioxide and the received flasksare treated with hydroquinone and 85% phosphoric acid to preventpolymerization of the monomers. After initial purification, the desiredalkyl cyanoacrylate can be further purified using multiple distillationor other purification techniques known to those in the art, such asvacuum distillation, spinning band column, and the like. The preferredalkyl cyanoacrylate monomers comprise at least 4 carbon atoms. Morepreferred cyanoacrylate compounds comprise alkyl groups having from 4 to10 carbon chains, for example, methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, deca, and the like. Especially preferredfor the invention are alkyl cyanoacrylates containing from 4 to 8carbons, for example, n-butyl, isobutyl, pentyl, 2-hexyl, 2-octyl, andthe like. The preferred amount of cyanoacrylate monomer is about 20% toabout 75%, by weight of the matrix-forming components. More preferably,the cyanoacrylate monomer comprises about 30% to about 70%, by weight ofthe matrix-forming components.

The alkyl cyanoacrylate monomer can be combined with a stabilizingcomponent. The stabilizing component can comprise an acidic stabilizer,a free radical inhibitor, an antioxidant, or a mixture thereof. Theacidic stabilizer can comprise at least one inorganic or organic acid.Examples of suitable inorganic acids include, but are not limited to,metallic acids, for example, phosphoric acid. Organic acids can include,but are not limited to, alkyl carboxylic acid, such as ethanoic acid,propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, and thelike, wherein the alkyl moiety ranges from 1 carbon, for example, aceticacid, through about 16 to 18 carbon atoms, for example, palmitic andstearic acid, respectively.

The free radical inhibitors commonly are low molecular weight electronacceptors. Examples of compounds that can inhibit free radicals in thecomposition include, but are not limited to, p-methoxyphenol,hydroquinone, glyoxides, and the like.

Antioxidants can reduce or inhibit the loss of electrons in thecomposition. Examples of antioxidants can include, but are not limitedto, vitamins A, C, and E, for example carotenoids, ascorbic acid, andalpha-, beta-, delta-, and gamma-tocopherols, acetates and estersthereof, and the like, or mixtures thereof.

The acidic stabilizer, free radical inhibitor, antioxidant, or mixturethereof, can be used to inhibit anionic polymerization and the rate ofsuch polymerization in the compound of the invention. The amount ofstabilizer used in the composition is determined relative to the amountof alkyl cyanoacrylate, typically in terms of parts per million. Forexample, hydroquinone can be included in the composition in a range ofabout 50 to 100 parts per million (ppm). Phosphoric acid typically canbe included in the composition of about 125 ppm to about 375 ppm. Theamount of stabilizing component including the acid stabilizer and/or thefree radical inhibitor, typically will be determined by one with skillin the art according to the components in the composition. Typically,the stabilizing component will comprise from about 50 to 500 ppm of thecomposition relative to the alkyl cyanoacrylate monomer. The alkylcyanoacrylate monomer and stabilizing component can be packaged ordelivered together, or as separate mixtures, with the solid-aggregatematerial.

The rheology modifying agent of the invention can be a non-cyanoacrylatepolymer. The non-cyanoacrylate polymer is typically pre-polymerized anddissolved in the alkyl cyanoacrylate liquid monomers or, morepreferably, dissolved in a plasticizer of the invention. Thenon-cyanoacrylate polymer is typically a polymer or copolymer compatiblewith the alkyl cyanoacrylate monomers. The non-cyanoacrylate polymer maybe selected from the group of poly(acrylates), poly(alkenes), poly(alkyloxides), poly(amides), poly(carbonates), cellulosic polymers andcopolymers, poly(dienes), poly(esters), poly(methacrylates),poly(saccharides), poly(siloxanes), poly(styrenes), poly(urethanes),poly(vinyl ethers), poly(vinyl esters), polymers and copolymers havinghigh iodine content, and other rubbery polymers compatible with alkylcyanoacrylate monomers, or mixtures thereof, particularly those thatimpart the desired properties on the liquid injectable and solidifiedcomposition.

One with skill in the art will be able to determine the amount ofpolymer to be included in the composition based on the relative weightof the polymer and the desired viscosity of the liquid composition.Typically, the polymers will have molecular weight of above 75,000. Morepreferably, the polymer will have a molecular weight of greater than200,000. The polymer can be included in a liquid medium, which cancomprise either a plasticizer solution or the alkyl cyanoacrylatemonomer itself.

The rheology modifying agent also can be a fine, inorganic particulatematerial. The rheology modifying agent is different from theradiopacifier and alters the rheological and cohesive properties of theembolic composition. The inorganic particulate material is typicallyincorporated with both the radiopacifier and the plasticizer. Theinorganic particulate material may be selected from the group consistingof fumed silica, silicatious earths, for example bentonite, or otherinorganic particulate gelling or suspending materials capable ofaltering the rheology of the embolic composition to possess propertiesof a thixotropic, pseudo-plastic, or plastic fluid. The size andconcentration of the rheology modifying agent can be selected from abroad range of such suitable particulate materials provided that theparticulate materials impart a thixotropic nature to the emboliccomposition. Suitable materials can include, for example, fumed silicaparticles of about 10 nanometers (0.1 micron) in diameter, and generallycan comprise particles of less than about 5 microns in diameter,depending on the nature of the particle selected.

An embolizing composition including an inorganic particulate rheologymodifying agent will exhibit a change in apparent viscosity upon movingfrom an environment with a first hydrodynamic shear rate to anenvironment having a second hydrodynamic shear rate. The effect soughtis typically referred to as “shear thinning behavior.” For example, theembolizing composition has a low apparent viscosity when flowing througha microcatheter and a relatively high apparent viscosity when it exitsthe microcatheter and is no longer flowing. This change in viscosity isnot associated with the polymerization of the alkyl cyanoacrylatemonomer, but is a property of the fluid embolizing composition inabsence of any chemical reaction.

A rheology modifying agent can impart properties of the liquidinjectable composition, such as improved viscosity, improvedcohesiveness, improved suspension, stability of dense radiopacifyingpowders, and additional radiopacity. A solidified composition includinga polymeric rheology modifying agent can have properties demonstratingimproved hydrolytic stability when compared to cyanoacrylatecompositions containing pre-polymerized cyanoacrylate.

A polymeric rheology modifying agent preferably comprises from about 0%to about 10%, by weight of the matrix-forming components. More preferredamounts of the rheology modifying agents are from about 1% to about 5%,by weight of the matrix-forming components.

An inorganic particulate rheology modifying agent would preferablycomprise from about 0% to about 75%, by volume of the solid-aggregatematerial. More preferably, the inorganic particulate rheology modifyingagent comprises from about 0% to about 40%, by volume of thesolid-aggregate material. The polymeric or inorganic particulaterheology modifying agents can be used in the embolic compositionindependently or in combination with one another.

The matrix-forming components include a plasticizer. The plasticizerimparts flexibility to the solidified composition and preventsbrittleness of the solidified polymer. The plasticizer can be a lowmolecular weight organic molecule, for example an organic ester, or alow molecular weight polymer. Suitable organic esters typically contain10 or more carbon atoms. Preferably, the organic esters contain fromabout 10 to about 18 carbon atoms. Suitable polymeric plasticizerstypically demonstrate a glass transition temperature below roomtemperature, for example, less than 20° C. The desired plasticizer iscompatible with the alkyl cyanoacrylate monomer and can impartproperties such as flexibility, elasticity, and minimal catheteradhesivity, to the solidified composition. Examples of plasticizerssuitable for the invention include, but are not limited to, aromaticesters, alkyl esters, phthalate esters, citrate esters, glycerol esters,plant derived oils, animal derived oils, silicone oils, iodinated oils,vitamins A, C, E, and acetates and esters thereof, and otherbiocompatible plasticizers, and the like, or mixtures thereof. Where theplasticizer is an iodinated oil, the plasticizer can be incorporatedinto the composition to enhance the radiopacity of the composition.

The plasticizer typically comprises about 10% to about 75%, by weight ofthe matrix-forming components. Preferably, the plasticizer comprises 30%to about 60%, by weight of the matrix-forming components.

The composition also can be rendered radiopaque by the inclusion of aseparate radiopacifier, a compound for imparting x-ray absorbing orscattering properties to the composition. The radiopacifier comprisesfine or sub-micron sized particles demonstrating high x-ray absorbance,either alone or in combination, with other components. The amount andsize of the particles can be determined by one with skill in the art inthe manner that is suitable for fluoroscopic visualization of theembolic material during injection through a suitable device, such as amicrocatheter, and for achieving the desired stability of the suspendedparticulates. More particularly, the radiopacifier will comprise acompound, wherein the particle size is typically less than one micron.The preferred particle size of a suitable radiopacifier is from about 50to about 500 nanometers in diameter.

Examples of compounds suitable for the radiopacifier component aretantalum (Ta), tantalum oxide (TaO), gold (Au), platinum (Pt), zirconium(Zr), zirconium oxide (ZrO), bismuth subcarbonate, and barium sulfate.The materials can be used in combination with iodinated oils or with aiodinated polymeric component or an iodinated plasticizer.

The radio-opaque particles and/or inorganic rheology modifying particlescan be treated in a manner consistent with improving their colloidal, orsuspension, stability. Stabilized suspensions maintain homogeneousproperties and can thereby reduce the incidence of encounteringdifferential flow properties and/or differential radiopacity of theembolic liquid prior to and during the process of injection. Theparticles can be pre-treated with the addition of chemical agents, whichcan either modify the surface chemistry of the particles by molecularadsorption or via a chemical reaction. The surface-modifying moleculesare typically adsorbed to or bonded to the surface of the particle,improving the stability of a suspension of the particles within thecomposition. The chemical pre-treatment of the particles typicallychanges the effective diameter of the particles or reducesparticle-particle interactions by (1) increasing steric repulsion, (2)decreasing electrostatic attractions, (3) changing the surface energy ofthe particles, or (4) adding or removing potential reactive sites on thesurface of the particles. The modifications generally are accomplishedby reactive coupling of long-chain molecules, for example C₆-polymers,to the particles, such as silane coupling to TaO or thiol coupling toAu; addition of a surfactant to the formulation, and preferably anon-ionic surfactant; addition of an ionic molecular species to theformulation, including for example species from simple salts to ionicpolymers; or the addition of any species that will adsorb to theparticles or influence electrostatic forces between particles as knownto those of skill in the art.

The solid-aggregate portion of the material is preferably storedseparately from the monomer. A hydrophobic carrier liquid may be used,for example, the plasticizer, an oil-based contrast agent, or otherhydrophobic low molecular weight biocompatible additives. The amount ofradiopacifier incorporated into the composition is about 5 to about 40volume percent based on the volume of the embolic composition. Morepreferably, the amount of radiopacifier is from about 8 to about 20volume percent based on the volume of the embolic composition.Alternatively, the amount of radiopacifier can be determined based onthe relative volume of the solid-aggregate material, which comprisesfrom about 5% to about 40%, by volume of the liquid composition.Preferably, the radiopacifier is present in an amount of from about 25%to about 100%, by volume of the solid-aggregate material. Morepreferably, the radiopacifier is present in an amount of from about 60%to about 100%, by volume of the solid-aggregate material.

The composition of the invention can be provided as individualcomponents or as mixtures of the individual components wherein the alkylcyanoacrylate monomer and the stabilizing component are combined andwherein the solid-aggregate material and the plasticizer also areintegrated. The rheology modifying polymer can be added to a mixturecontaining the monomer and/or a mixture containing the plasticizer. Whenthe composition is provided as a single composition, the plasticizer andthe solid-aggregate material are mixed before contacting thesolid-aggregate material with the alkyl cyanoacrylate monomer.

Therefore, as previously described herein, the composition of theinvention can comprise a matrix-forming component and optionally asolid-aggregate material, wherein the matrix-forming component comprisesliquid cyanoacrylate monomers and at least a stabilizer and aplasticizer. The solid-aggregate material comprises a radiopacifier, andthe rheology modifying agent is incorporated into the composition eitheras a matrix-forming component, as a solid-aggregate material, or as aseparate component altogether.

Typically, the matrix-forming component of the composition comprisesfrom about 60% to about 94%, by volume of the embolic composition. Thesolid-aggregate material comprises from about 5% to about 40%, by volumeof the embolic composition. Preferred and more preferred compositions ofthe invention are provided in the table below:

Preferred and More Preferred Compositions with Rheological ModifyingAgent¹ Matrix-Forming Component² Solid-Aggregate Material More MorePrefer Prefer Prefer Prefer Ingredient (w/w %) (w/w %) Ingredient (v/v%) (v/v %) monomer³ 20-75 30-70 radiopacifier 25-100 60-100 plasticizer10-75 30-60 particulate 0-75 0-40 rheology modifying agent polymer  0-101-5 rheology modifying agent ¹w/w % represents “by weight” percentrelative to the matrix-forming components; v/v % represents “by volume”percent relative to the solid-aggregate material ²A stabilizer also isincluded in minimal amounts of parts per million range and, therefore,is not represented in the table. ³“Monomer” refers to an alkylcyanoacrylate monomer.

The composition of the present invention can be administered with anysuitable method. Typically, the components of the composition areprovided either separately or in combination as previously described.The components of the composition are mixed together to form the emboliccomposition, which can be delivered by any suitable method. Suitablemethods for administering the composition will deliver the liquidinjectable composition preferably directly to the delivery site or thelocation of the diseased, damaged, or otherwise compromised vasculatureor tissue. Upon contact with an ionic environment of the delivery site,for example blood, the composition will form a solidified composition,or embolic block.

Typically, the composition of the invention is delivered in a catheterdevice that is prefilled with a nonionic solution, for example, a 5%dextrose solution. Commercially available methods can include needles,catheter devices, or stereotaxic placement devices, preferably inconjunction with an imaging technology that provides the practitionerwith guidance as to the placement of the composition. Some devices andmethods already known to those of skill in the art include, for example,in U.S. Pat. No. 5,925,683, which discloses a method for introducingliquid embolic agents/solutions into the human body to form precipitatedembolic occlusion masses; U.S. Pat. No. 5,702,361, which describes amethod of embolizing a vascular site in a patient's blood vesselscomprising introducing via a catheter a non-particulate agent at thevasculature site; and U.S. Pat. No. 5,882,334, which describes acatheter assembly for delivering embolic compositions.

The compositions can be used advantageously in conjunction with anymethod that employs an embolizing agent, occluding agent, bulking agent,or such composition that creates an embolic block, occlusion, orincrease in tissue volume. More particularly, the embolic agentselectively creates a blockage in the lumen of a blood vessel, duct,fistula, or other like body passages. A preferred method for deliveringthe embolic agent would involve delivering the liquid emboliccomposition via a microcatheter into the vascular region to beembolized.

In the case of aneurysm treatment, placement of a secondary emboliccontainment device, either temporarily or permanently, is preferred.Temporary aneurysmal neck occlusion devices can be achieved, forexample, using a balloon catheter placed in a position such that theaneurysm neck is sufficiently occluded as to allow the catheter to beinserted into the aneurysm and to prevent the escape of any of theembolic composition. Permanent implantable devices also can be used toprevent escape of the embolic composition, for example, a stent or aneck-bridging device, such as the TRI-SPAN COIL™ intracranial aneurysmdevice (Target Therapeutics, Inc., Fremont, Calif., U.S.A.) or any otherdevice intended to prevent the migration of embolic materials or embolicconstructs out of the aneurysm. The material also can be delivered usingdevices intended to both deliver and contain embolic materials, such asthe device described in U.S. Pat. No. 5,795,331.

The composition has the desired viscosity and cohesive characteristicsto administer into an ionic fluid environment, such as blood. Thecomposition forms a solid structure upon contact with the ionicenvironment. In addition, the present invention is radiopaque whichallows for observation by a practitioner with x-ray or other like orequivalent imaging techniques. The composition and method of the presentinvention can be advantageously used to block blood flow to certaintissues, areas, or cavities in the vasculature. Such treatment can beused to alleviate symptoms experienced because of AVM, for example,bleeding, seizures, or cerebral or other hemorrhage. The method canstabilize or mitigate rupture of an aneurysm when properly employed.

Although the present invention has been described with reference to apreferred embodiment, those skilled in the art will recognize thatchanges can be made in form and detail without departing from the spiritand scope of the present invention. As such, it is intended that thedetailed description is regarded as illustrative rather than limitingand the invention is defined by the appended claims.

1. A composition comprising: a matrix-forming component comprising alkylcyanoacrylate monomers, a stabilizer, and a plasticizer; a solidaggregate material comprising a radiopacifier; and a polymericnon-cyanoacrylate rheology modifying agent. 2-3. (canceled)
 4. Thecomposition of claim 1, wherein the polymeric non-cyanoacrylate rheologymodifying agent is a polymer or copolymer compound soluble in the alkylcyanoacrylate monomers or in the plasticizer.
 5. The composition ofclaim 1, wherein the polymeric non-cyanoacrylate rheology modifyingagent is selected from the group consisting of poly(acrylates),poly(alkenes), poly(alkyl oxides), poly(amides), poly(carbonates),cellulosic polymers and copolymers, poly(dienes), poly(esters),poly(methacrylates), poly(saccharides), poly(siloxanes), poly(styrenes),poly(urethanes), poly(vinyl ethers), poly(vinyl esters), polymers andcopolymers having high iodine content, and mixtures thereof. 6.(canceled)
 7. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent has a molecular weight of atleast 75,000.
 8. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent has a molecular weight of atleast 200,000.
 9. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent and the plasticizer is thesame material.
 10. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent comprises up to about 10%, byweight of the matrix-forming components.
 11. The composition of claim 1,wherein the polymeric non-cyanoacrylate rheology modifying agentcomprises about 1% to about 5%, by weight of the matrix-formingcomponents.
 12. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent is a particulate materialcomprising about 0% to about 75% by volume of the solid-aggregatematerials.
 13. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent is a particulate materialcomprising about 0% to about 40%, by volume of the solid-aggregatematerials.
 14. The composition of claim 1, wherein the polymericnon-cyanoacrylate rheology modifying agent comprises inorganic particleswith surface-modifying molecules adsorbed to or bonded to the surfacesof said particles for improving the stability of a suspension of saidparticles within said composition.
 15. The composition of claim 1,wherein the alkyl cyanoacrylate monomer is a compound of the formulaH₂C═C(CN)—C(O)OR, wherein R is an alkyl group of about 1 to about 18carbons.
 16. The composition of claim 15, wherein the group representedby R is an alkyl group of about 4 to about 10 carbons.
 17. Thecomposition of claim 1, wherein the alkyl cyanoacrylate monomer ispresent in an amount of from about 20% to about 75%, by weight of thematrix-forming component.
 18. The composition of claim 1, wherein thealkyl cyanoacrylate monomer is present in an amount of from about 30% toabout 70%, by weight of the matrix-forming component.
 19. Thecomposition of claim 1, wherein the stabilizer is an inorganic acid, anorganic acid, a free radical inhibitor, an antioxidant, or a mixturethereof.
 20. The composition of claim 1, wherein the stabilizer ispresent in an amount of from about 50 ppm to about 500 ppm.
 21. Thecomposition of claim 1, wherein the radiopacifier is selected from thegroup consisting of Ta, TaO, Au, Pt, Zr, ZrO, bismuth subcarbonate, andbarium sulfate.
 22. The composition of claim 1, wherein theradiopacifier comprises radio-opaque particles with surface-modifyingmolecules adsorbed to or bonded to the surfaces of said particles forimproving the stability of a suspension of said particles within saidcomposition.
 23. The composition of claim 1, wherein the radiopacifieris about 25% to about 100%, by volume of the solid-aggregate material.24. The composition of claim 1, wherein the radiopacifier is about 60%to about 100%, by volume of the solid-aggregate material.
 25. Thecomposition of claim 1, wherein the plasticizer is selected from thegroup consisting of organic esters containing 10 or more carbon atomsand polymeric compounds, having a glass transition temperature less than20° C.
 26. The composition of claim 1, wherein the plasticizer isselected from the group consisting of aromatic esters, alkyl esters,phthalate esters, citrate esters, glycerol esters, plant derived oils,animal derived oils, silicone oils, iodinated oils, vitamins A, C, E,and acetates and esters thereof, and mixtures thereof.
 27. Thecomposition of claim 1, wherein the plasticizer is about 10% to about75%, by weight of the matrix-forming component.
 28. The composition ofclaim 1, wherein the plasticizer is about 30% to about 60%, by weight ofthe matrix-forming component. 29-37. (canceled)